Novel 3,4-disubstituted 1,2,3,6-tetrahydropyridine derivatives

ABSTRACT

The invention relates to novel 3,4-disubstituted 1,2,3,6-tetrahydropyridine derivatives and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin.

The invention relates to novel compounds of the general formula I. Theinvention also concerns related aspects including processes for thepreparation of the compounds, pharmaceutical compositions containing oneor more compounds of formula I and especially their use as renininhibitors in cardiovascular events and renal insufficiency.Furthermore, some of these compounds can be regarded as inhibitors ofother aspartyl proteases and might therefore be useful as inhibitors ofplasmepsins to treat malaria and as inhibitors of Candida albicanssecreted aspartyl proteases to treat fungal infections.

In the renin-angiotensin system (RAS) the biologically activeangiotensin II (Ang II) is generated by a two-step mechanism. The highlyspecific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I),which is then further processed to Ang II by the less specificangiotensin-converting enzyme (ACE). Ang II is known to work on at leasttwo receptor subtypes called AT₁ and AT₂. Whereas AT₁ seems to transmitmost of the known functions of Ang II, the role of AT₂ is still unknown.

Modulation of the RAS represents a major advance in the treatment ofcardiovascular diseases. ACE inhibitors and AT₁ blockers have beenaccepted to treat hypertension (Waeber B. et al., “The renin-angiotensinsystem: role in experimental and human hypertension”, in Berkenhager W.H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier SciencePublishing Co, 1996, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5,247S). In addition, ACE inhibitors are used for renal protection(Rosenberg M. E. et al., Kidney International, 1994, 45, 403; Breyer J.A. et al., Kidney International, 1994, 45, S156), in the prevention ofcongestive heart failure (Vaughan D. E. et al., Cardiovasc. Res., 1994,28, 159; Fouad-Tarazi F. et al., Am. J. Med., 1988, 84 (Suppl. 3A), 83)and myocardial infarction (Pfeffer M. A. et al., N. Engl. J. Med., 1992,327, 669).

The rationale to develop renin inhibitors is the specificity of renin(Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrateknown for renin is angiotensinogen, which can only be processed (underphysiological conditions) by renin. In contrast, ACE can also cleavebradykinin besides Ang I and can be by-passed by chymase, a serineprotease (Husain A., J. Hypertens., 1993, 11, 1155). In patientsinhibition of ACE thus leads to bradykinin accumulation causing cough(5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%)(Israili Z. H. et al., Annals of Internal Medicine, 1992, 117, 234).Chymase is not inhibited by ACE inhibitors. Therefore, the formation ofAng II is still possible in patients treated with ACE inhibitors.Blockade of the AT₁ receptor (e.g. by losartan) on the other handoverexposes other AT-receptor subtypes to Ang II, whose concentration isdramatically increased by the blockade of AT₁ receptors. This may raiseserious questions regarding the safety and efficacy profile of AT,receptor antagonists. In summary, renin inhibitors are not only expectedto be different from ACE inhibitors and AT₁ blockers with regard tosafety, but more importantly also with regard to their efficacy to blockthe RAS.

Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994,12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has beencreated with renin inhibitors because of their insufficient oralactivity due to their peptidomimetic character (Kleinert H. D.,Cardiovasc. Drugs, 1995, 9, 645). The clinical development of severalcompounds has been stopped because of this problem together with thehigh cost of goods. Only one compound containing four chiral centers hasentered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493;Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, metabolicallystable, orally bioavailable and sufficiently soluble renin inhibitorsthat can be prepared on a large scale are missing and sought. Recently,the first non-peptide renin inhibitors were described which show high invitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; PatentApplication WO97/09311; Marki H. P. et al., II Farmaco, 2001, 56, 21).However, the development status of these compounds is not known.

The present invention relates to the unexpected identification of renininhibitors of a non-peptidic nature and of low molecular weight. Orallyactive renin inhibitors of long duration of action which are active inindications beyond blood pressure regulation where the tissularrenin-chymase system may be activated leading to pathophysiologicallyaltered local functions such as renal, cardiac and vascular remodeling,atherosclerosis, and possibly restenosis, are described.

In particular, the present invention relates to novel compounds of thegeneral formula I.

wherein

X and W represent independently a nitrogen atom or a CH-group;

V represents —(CH₂)_(r); -A-(CH₂)_(s)—; —CH₂-A-(CH₂)_(t)—;—(CH₂)_(s)-A-; —(CH₂)₂-A-(CH₂)_(u)—; -A-(CH₂)_(v)—B—;—CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—B—;—CH₂—CH₂—CH₂-A-CH₂—CH₂—; —CH₂—CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—CH₂—;—CH₂-A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—CH₂—B—; —CH₂—CH₂-A-CH₂—CH₂—B—;

A and B independently represent —O—; —S—; —SO—; —SO₂—;

U represents aryl; heteroaryl;

T represents —CONR¹—; —(CH₂)_(p)OCO—; —(CH₂)_(p)N(R¹)CO—;—(CH₂)_(p)N(R₁)SO₂—; —COO—; —(CH₂)_(p)OCONR¹—; —(CH₂)_(p)N(R¹′)CONR¹—;

Q represents lower alkylene; lower alkenylene;

M represents hydrogen; cycloalkyl; aryl; heterocyclyl; heteroaryl;aryl-O(CH₂)_(v)R²; heteroaryl-O(CH₂)_(v)R²; aryl-O(CH₂)₂O(CH₂)_(w)R²;heteroaryl-(CH₂)₂O(CH₂)_(w)R²; aryl-OCH₂CH(R⁵)CH₂R²;heteroaryl-OCH₂CH(R⁵)CH₂R²;

R¹ and R¹′ independently represent hydrogen; lower alkyl; lower alkenyl;lower alkinyl; cycloalkyl; aryl; cycloalkyl-lower alkyl;

R² represents —OH, lower alkoxy, —OCOR³, —COOR³, —NR³R³, —OCONR³R³′,—NCONR³R³′, cyano, —CONR³R³′, SO₃H, —SONR³R³′, —CO-morpholin-4-yl,—CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH₂, —NR⁴R⁴′, with theproviso that a carbon atom is attached at the most to one heteroatom incase this carbon atom is sp³-hybridized;

R³ and R³′ independently represent hydrogen; lower alkyl; lower alkenyl;cycloalkyl; cycloalkyl-lower alkyl;

R⁴ and R⁴′ independently represent hydrogen; lower alkyl; cycloalkyl;cycloalkyl-lower alkyl; hydroxy-lower alkyl; —COOR²; —CONH₂;

R⁵ represents —OH, —OR²; —OCOR²; —OCOOR²; or R⁵ and R² form togetherwith the carbon atoms to which they are attached a 1,3-dioxolane ringwhich is substituted in position 2 with R³ and R³′; or R₅ and R² formtogether with the carbon atoms to which they are attached a1,3-dioxolan-2-one ring;

p is the integer 1, 2, 3 or 4;

r is the integer 3, 4, 5 or 6;

s is the integer 2, 3, 4 or 5;

t is the integer 1, 2, 3 or 4;

u is the integer 1, 2 or 3;

v is the integer 2, 3 or 4;

w is the integer 1 or 2;

and optically pure enantiomers, mixtures of enantiomers such asracemates, diastereomers, mixtures of diastereomers, diastereomericracemates, mixtures of diastereomeric racemates, and the meso-form; aswell as pharmaceutically acceptable salts, solvent complexes andmorphological forms.

In the definitions of general formula I—if not otherwise stated—the termlower alkyl, alone or in combination with other groups, means saturated,straight and branched chain groups with one to seven carbon atoms,preferably one to four carbon atoms that can be optionally substitutedby halogens. Examples of lower alkyl groups are methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl andheptyl. The methyl, ethyl and isopropyl groups are preferred.

The term lower alkoxy refers to a R—O-group, wherein R is a lower alkyl.Examples of lower alkoxy groups are methoxy, ethoxy, propoxy,iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.

The term lower alkenyl, alone or in combination with other groups, meansstraight and branched chain groups comprising an olefinic bond and twoto seven carbon atoms, preferably two to four carbon atoms, that can beoptionally substituted by halogens. Examples of lower alkenyl are vinyl,propenyl or butenyl.

The term lower alkinyl, alone or in combination with other groups, meansstraight and branched chain groups comprising a triple bond and two toseven carbon atoms, preferably two to four carbon atoms, that can beoptionally substituted by halogens. Examples of lower alkinyl areethinyl, propinyl or butinyl.

The term lower alkylene, alone or in combination with other groups,means straight and branched divalent chain groups with one to sevencarbon atoms, preferably one to four carbon atoms, that can beoptionally substituted by halogens. Examples of lower alkylene areethylene, propylene or butylene.

The term lower alkenylene, alone or in combination with other groups,means straight and branched divalent chain groups comprising an olefinicbond and two to seven carbon atoms, preferably two to four carbon atoms,that can be optionally substituted by halogens. Examples of loweralkenylene are vinylene, propenylene and butenylene.

The term lower alkylenedioxy, refers to a lower alkylene substituted ateach end by an oxygen atom. Examples of lower alkylenedioxy groups arepreferably methylenedioxy and ethylenedioxy.

The term lower alkylenoxy refers to a lower alkylene substituted at oneend by an oxygen atom. Examples of lower alkylenoxy groups arepreferably ethylenoxy and propylenoxy.

The term halogen means fluorine, chlorine, bromine or iodine, preferablyfluorine, chlorine and bromine.

The term cycloalkyl alone or in combination, means a saturated cyclichydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which can beoptionally mono-, di-, or trisubstituted independently by lower alkyl,lower alkenyl, lower alkenylene, lower alkoxy, lower alkylenoxy, loweralkylenedioxy, hydroxy, halogen, —CF₃, —NR¹R¹′, —NR¹C(O)R¹′,—NR¹S(O)₂R¹′, —C(O)NR¹R¹′, lower alkylcarbonyl, —COOR¹, —SR¹, —SOR¹,—SO₂R¹, —SO₂NR¹R¹′. The cyclopropyl group is a preferred group.

The term aryl, alone or in combination, relates to the phenyl, thenaphthyl or the indanyl group, preferably the phenyl group, which can beoptionally mono-, di-, tri-, tetra- or pentasubstituted independently bylower alkyl, lower alkenyl, lower alkinyl, lower alkenylene or loweralkylene forming with the aryl ring a five- or six-membered ring, loweralkoxy, lower alkylenedioxy, lower alkylenoxy, hydroxy, hydroxy-loweralkyl, halogen, cyano, —CF₃, —OCF₃, —NR¹R¹′, —NR¹R¹′-lower alkyl,—NR¹C(O)R¹′, —NRIS(O)₂R¹′, —C(O)NR¹R¹′, —NO₂, lower alkylcarbonyl,—COOR¹, —SR¹, —S(O)R¹, —S(O)₂R¹, —SO₂NR¹R¹′, benzyloxy. Preferredsubstituents are halogens, lower alkoxy, lower alkyl.

The term aryloxy refers to an Ar—O-group, wherein Ar is an aryl. Anexample of aryloxy groups is phenoxy.

The term heterocyclyl, alone or in combination, means saturated orunsaturated (but not aromatic) five-, six- or seven-membered ringscontaining one or two nitrogen, oxygen or sulfur atoms which may be thesame or different and which rings can be optionally substituted withlower alkyl, hydroxy, lower alkoxy and halogen. The nitrogen atoms, ifpresent, can be substituted by a COOR² group. Examples of such rings arepiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl,tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl,dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.

The term heteroaryl, alone or in combination, means six-memberedaromatic rings containing one to four nitrogen atoms; benzofusedsix-membered aromatic rings containing one to three nitrogen atoms;five-membered aromatic rings containing one oxygen, one nitrogen or onesulfur atom; benzofused five-membered aromatic rings containing oneoxygen, one nitrogen or one sulfur atom; five-membered aromatic ringscontaining one oxygen and one nitrogen atom and benzofused derivativesthereof; five-membered aromatic rings containing a sulfur and a nitrogenor an oxygen atom and benzofused derivatives thereof; five-memberedaromatic rings containing two nitrogen atoms and benzofused derivativesthereof; five-membered aromatic rings containing three nitrogen atomsand benzofused derivatives thereof, or a tetrazolyl ring. Examples ofsuch ring systems are furanyl, thiophenyl, pyrrolyl, pyridinyl,pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl,thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl,isoxazolyl, coumarinyl, benzothiophenyl, quinazolinyl, quinoxalinyl.Such rings may be adequatly substituted with lower alkyl, lower alkenyl,lower alkinyl, lower alkylene, lower alkenylene, lower alkylenedioxy,lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy, halogen,cyano, —CF₃, —OCF₃, —NR¹R¹′, —NR¹R¹′-lower alkyl, —N(R¹)COR¹,—N(R¹)SO₂R¹, —CONR¹R¹′, —NO₂, lower alkylcarbonyl, —COOR¹, —SR¹,—S(O)R¹, —S(O)₂R¹, —SO₂NR¹R¹′, another aryl, another heteroaryl oranother heterocyclyl and the like.

The term heteroaryloxy refers to a Het-O group, wherein Het is aheteroaryl.

It is understoood that the substituents outlined relative to theexpressions cycloalkyl, heterocyclyl, heteroaryl and aryl have beenomitted in the definitions of the general formula I and in claims 1 to 6for clarity reasons but the definitions in formula I and in claims 1 to6 should be read as if they are included therein.

The expression pharmaceutically acceptable salts encompasses eithersalts with inorganic acids or organic acids like hydrochloric orhydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formicacid, acetic acid, maleic acid, tartaric acid, benzoic acid,methanesulfonic acid, p-toluenesulfonic acid, and the like that are nontoxic to living organisms or in case the compound of formula I is acidicin nature with an inorganic base like an alkali or earth alkali base,e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and thelike.

Compounds of the invention also include nitrosated compounds of thegeneral formula I that have been nitrosated through one or more sitessuch as oxygen (hydroxyl condensation), sulfur (sulfflydrylcondensation) and/or nitrogen. The nitrosated compounds of the presentinvention can be prepared using conventional methods known to oneskilled in the art. For example, known methods for nitrosating compoundsare described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO98/19672; WO 98/21193; WO 99/00361 and Oae et al, Org. Prep. Proc. Int.,15(3): 165-198 (1983), the disclosures of each of which are incorporatedby reference herein in their entirety.

The compounds of the general formula I can contain one or moreasymmetric carbon atoms and may be prepared in form of optically pureenantiomers, mixtures of enantiomers such as racemates, diastereomers,mixtures of diastereomers, diastereomeric racemates, mixtures ofdiastereomeric racemates, and the meso-form and pharmaceuticallyacceptable salts thereof.

The present invention encompasses all these forms. Mixtures may beseparated in a manner known per se, i.e. by column chromatography, thinlayer chromatography, HPLC or crystallization.

A group of preferred compounds of general formula I are those wherein X,W, V, and U, are as defined in general formula I wherein

T is —CONR¹—;

Q is a methylene;

M is aryl; heteroaryl; aryl-O(CH₂)_(v)R²; heteroaryl-O(CH₂)_(v)R².

Another group of more preferred compounds of general formula I are thosewherein X, W, T, Q, and M are as defined in general formula I wherein

V is one of the following groups:

—CH₂CH₂O—; —CH₂CH₂CH₂O—; —OCH₂CH₂O—;

and U is as defined in general formula I above.

Another group of even more preferred compounds of general formula I arethose wherein V, U, T, Q, and M are as defined in general formula I andwherein

X and W represent —CH—.

Another group of more preferred compounds of general formula I are thosewherein X, W, V, Q, T, and M are as defined in general formula I andwherein

U is a mono-, di-, or trisubstituted phenyl or heteroaryl. Preferredsubstituents are independently halogen, lower alkyl, lower alkoxy, CF₃.Especially preferred compounds of general formula I are those selectedfrom the group consisting of:

-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid cyclopropyl-(2-fluorobenzyl)amide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid (2-chlorobenzyl)ethylamide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid (2-chlorobenzyl)cyclopropylamide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid cyclopropyl-(3-methoxybenzyl)amide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid cyclopropyl-(2-methoxybenzyl)amide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylic    acid cyclopropyl-(5-fluoro-2-methoxybenzyl)amide;-   (rac.)-4-{-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid (2-chloro-6-fluorobenzyl)cyclopropylamide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid (2-bromobenzyl)cyclopropylamide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid cyclopropyl-(2,3-dimethylbenzyl)amide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]-henyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylic    acid (3,5-bis-trifluoromethylbenzyl)cyclopropylamide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid (2-chloro-5-trifluoromethylbenzyl)cyclopropylamide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid (2-chloro-3,6-difluorobenzyl)cyclopropylamide;-   (rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylic    acid cyclopropyl-(3-methylbenzyl)amide.

The compounds of general formula I and their pharmaceutically acceptablesalts may be used as therapeutics e.g. in form of pharmaceuticalcompositions. These pharmaceutical compositions containing at least onecompound of general formula I and usual carrier materials and adjuvantsmay especially be used in the treatment or prophylaxis of disorderswhich are associated with a dysregulation of the renin angiotensinsystem (RAS), comprising cardiovascular and renal diseases. Examples ofsuch diseases are hypertension, congestive heart failure, pulmonaryheart failure, coronary diseases, cardiac insufficiency, renalinsufficiency, renal or myocardial ischemia, atherosclerosis, and renalfailure. They can also be used to prevent restenosis after balloon orstent angioplasty, to treat erectile dysfunction, glomerulonephritis,renal colic, and glaucoma. Furthermore, they can be used in the therapyand the prophylaxis of diabetic complications, complications aftervascular or cardiac surgery, complications of treatment withimmunosuppresive agents after organ transplantation, complications ofcyclosporin treatment, as well as other diseases presently known to berelated to the RAS.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are related to the RASsuch as hypertension, congestive heart failure, pulmonary hypertension,cardiac insufficiency, renal insufficiency, renal or myocardialischemia, atherosclerosis, renal failure, erectile dysfunction,glomerulonephritis, renal colic, glaucoma, diabetic complications,complications after vascular or cardiac surgery, restenosis,complications of treatment with immunosuppresive agents after organtransplantation, and other diseases which are related to the RAS, whichmethod comprises administering a compound according of formula I to ahuman being or animal.

The invention further relates to the use of compounds of general formulaI as defined above for the treatment and/or prophylaxis of diseaseswhich are associated with the RAS such as hypertension, congestive heartfailure, pulmonary hypertension, cardiac insufficiency, renalinsufficiency, renal or myocardial ischemia, atherosclerosis, renalfailure, erectile dysfunction, glomerulonephritis, renal colic,glaucoma, diabetic complications, complications after vascular orcardiac surgery, restenosis, complications of treatment withimmunosuppresive agents after organ transplantation, and other diseasespresently known to be related to the RAS.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprophylaxis of diseases which are associated with the RAS such ashypertension, coronary diseases, cardiac insufficiency, renalinsufficiency, renal and myocardial ischemia, and renal failure. Thesemedicaments may be prepared in a manner known per se.

The compounds of formula I may also be used in combination with one ormore other pharmacologically active compounds e.g. with other renininhibitors, with ACE-inhibitors, angiotensin II receptor antagonists,endothelin receptor antagonists, vasodilators, calcium antagonists,potassium activators, diuretics, sympatholitics, beta-adrenergicantagonists, and neutral endopeptidase inhibitors, alpha-adrenergicantagonists, for the treatment of disorders as above-mentioned.

All forms of prodrugs leading to an active component comprised ingeneral formula I are included in the present invention.

The compounds of general formula I can be manufactured by the methodsgiven below, by the methods given in the examples or by analogousmethods.

Preparation of the Precursors:

Precursors are compounds that were prepared as key intermediates and/orbuilding blocks and which were suitable for further transformations inparallel chemistry.

Ideal starting materials are any commercially available4-oxo-piperidine-3-carboxylic acid ester derivatives, for instance1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester, possibly as asalt. For practical purposes, a transesterification (for instanceaccording to Seebach D., et al., Synthesis, 1982, 138) to another esterderivative A (wherein R^(a) is optionally a lower alkyl, a loweralkenyl, or a benzyl group), thereafter a change in the N-protectinggroup (PG: all abreviations are outlined at the beginning of the chapterExamples) to a derivative of type B, may be necessary (Scheme I).

Formation of the vinyl triflate C, followed by a coupling catalysed by aPd(0) complex leads to tetrahydropyridine derivatives of type D, whereinR^(b) optionally represents any U-V group as defined in general formulaI or a chemical precursor of such a group (Scheme 2).

If, for instance, R^(b) is a linker ending with a silanyl ether,compounds of type D can be deprotected to compounds of type E, thencoupled to a phenol or aromatic alcohol using a Mitsunobu reaction,leading to derivatives of type F wherein V and U have the meaning givenin general formula I above (Scheme 3). The ester F can then be cleavedunder basic conditions to lead to precursor G, whereas the double bondwould partially or completely be shifted to the 4,5-position.

Other chemistry may be used in analogy to patent applicationsWO03/093267 and WO04/002957. This allows to prepare other compoundsincluded in general formula I.

Preparation of Final Compounds

A compound of type G can be coupled to the amine to yield to thecorresponding amides wherein V, U and M have the meaning given ingeneral formula I above. Removal of the N-protecting group (PG) leads tothe final compounds wherein V, U, Q and M have the meaning given ingeneral formula I above (Scheme 4). If the precursor G is mixed to thecorresponding constitutional isomer having a double bond at the3,4-position, both compounds may be now separated by flashchromatography, using some ammoniac as co-eluent, or by HPLC.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral, or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragees, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable acid addition salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants in a manner known per se.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragees and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injections are, for example, water, alcohols,polyols, glycerols and vegetable oils. Suitable carrier materials forsuppositories are, for example, natural or hardened oils, waxes, fatsand semi-liquid or liquid polyols. Suitable carrier materials fortopical preparations are glycerides, semi-synthetic and syntheticglycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquidfatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 50 mg to about 500 mg, comes into consideration. Forchildren the dosage has to be adapted to the body weight and age.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 5-200 mg of a compound of formula I.

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

General Remarks

The following compounds were prepared according to the proceduresdescribed for the synthesis of compounds encompassed by the generalformula 1. All compounds were characterized by ¹H-NMR (300 MHz) andoccasionally by ¹³C-NMR (75 MHz) (Varian Oxford, 300 MHz; chemicalshifts are given in ppm relative to TMS), by LC-MS: A: 2 min<t_(R)<10min; (Waters Micromass; ZMD-platform with ESI-probe with Alliance 2790HT; Column: 2×30 mm, Gromsil ODS4, 3 μM, 120A; Gradient: 0-100%acetonitril in water, 6 min, with 0.05% formic acid, flow: 0.45 mL/min;t_(R) given in min.), B: 0.1 min<t_(R)<2 min; (Finnigan AQA withESI-probe with HP 110 DAD and HP110 binary pump; column: DevelosilRP-AQUEOUS, 5 μM, 4.6 mm×50 mm; gradient: 5-95% methanol in water (0.04%TFA), 1 min, 95% methanol in water (0.04% TFA) 0.4 min, 4.5 mL/min.), byTLC (TLC-plates from Merck, Silica gel 60 F₂₅₄). Only TLC and LC-MS dataare given hereby.

Abbreviations

-   ACE Angiotensin Converting Enzyme-   Ang Angiotensin-   aq. aqueous-   Bn Benzyl-   Boc tert-Butyloxycarbonyl-   BSA Bovine serum albumine-   BuLi n-Butyllithium-   DIPEA Diisopropylethylamine-   DMAP 4-N,N-Dimethylaminopyridine-   DMSO Dimethylsulfoxide-   EDC-HCl Ethyl-N,N-dimethylaminopropylcarbodiimide hydrochloride-   EIA Enzyme immunoassay-   eq. equivalent-   Et Ethyl-   EtOAc Ethyl acetate-   FC Flash Chromatography-   HOBt Hydroxybenzotriazol-   MeOH Methanol-   org. organic-   PBS Phosphate Buffer Saline-   PG protecting group-   Ph Phenyl-   RAS Renin Angiotensin System-   RP18 Reversed phase column, filled with C₁₈ hydrocarbon-   rt room temperature-   sol. Solution-   TBDMS tert-Butyldimethylsilyl-   Tf Trifluoromethylsulfonyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin Layer Chromatography    Preparation of the Precursors

4-Oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(B)

A suspension of 1-benzyl-4-oxopiperidine-3-carboxylic acid methyl esterhydrochloride (5.00 g, 17.6 mmol), triethylamine (2.45 mL, 17.6 mmol)and Boc₂O (4.20 g, 20.0 mmol) in EtOH (30 mL) was purged with N₂. Pd/C(10%, 600 mg) was added and the suspension purged with H₂. The reactionmixture was stirred under an H₂-atmosphere for 24 h and then filteredthrough Celite. The filtrate was evaporated under reduced pressure.Purification of the residue by FC (EtOAc/heptane 1:4→2:3) yielded thetitle compound (4.02 g, 89%). R_(f)=0.60 (EtOAc/heptane 1:1). LC-MS:R_(t)=1.09 min, ES+=202.03.

4-Trinfluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (C)

To a sol. of compound B (4.00 g, 15.6 mmol) in THF (100 mL) at 0° C. wasadded NaH (suspension in oil, 55-65%, 1.20 g, about 31 mmol). Thesuspension was stirred for 30 min at 0° C. and Tf₂NPh (8.27 g, 23.1mmol) was added. The ice bath was removed and the reaction mixturestirred for 3 days at rt. Ice was added and the solvents were removedunder reduced pressure. The residue was diluted with EtOAc and washedwith aq. 10% Na₂CO₃. The org. extracts were dried over MgSO₄, filteredand the solvent removed under reduced pressure. Purification of theresidue by FC (EtOAc/heptane 1:4) yielded the title compound (5.19 g,86%). LC-MS: R_(t)=1.17, ES+=374.96.

4-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (D)

To a sol. of [3-(4-bromophenyl)propoxy]-tert-butyldimethylsilane(Kiesewetter D. O., Tetrahedron Asymmetry, 1993, 4, 2183; 6.19 g, 19.7mmol) in THF (100 mL) at −78° C. was added n-BuLi (1.5M in hexane, 14.0mL, 21.0 mmol). The sol. was stirred at −780C for 30 min and ZnCl₂ (1Min THF, 22.3 mL, 22.3 mmol) was added. The resulting sol. was allowed towarm to rt and compound C (5.10 g, 13.1 mmol) and Pd(PPh₃)₄ (300 mg,0.26 mmol) were added. After 20 min at rt ice was added to the reactionmixture. The solvents were removed under reduced pressure and theresidue diluted with EtOAc. This mixture was washed with aq. 1 M NaOH.The org. extracts were dried over MgSO₄, filtered and the solventsremoved under reduced pressure. Purification of the residue by FC(EtOAc/heptane 1:9) led to the title compound (5.77 g, 90%). LC-MS:R_(f)=7.27 min, ES+=512.54.

4-[4-(3-Hydroxypropyl)phenyl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (E)

TBAF (1.90 g, 6.00 mmol) was added to a sol. of compound D (1.95 g, 4.00mmol) in THF (40 mL). The reaction mixture was stirred for 6 h at rt anddiluted with EtOAc. The resulting mixture was washed with water andbrine. The org. extracts were dried over MgSO₄, filtered and thesolvents removed under reduced pressure. Purification of the residue byFC (EtOAc/heptane 2:3) yielded the title compound (1.27 g, 84%). LC-MS:R_(t)=1.06, ES+=376.18.

4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (F)

A sol. of compound E (4.7 g, 12.5 mmol), 2,3,6-trifluorophenol (3.7 g,25.0 mmol), azodicarboxylic dipiperidine (6.32 g, 34.2 mmol),tri-n-butylphosphine (85%, 9.3 mL, 37.6 mmol) and DIPEA (0.035 mL, 0.20mmol.) in toluene (20 mL) was stirred for 1 h at rt, then for 2 h at 60°C. The reaction mixture was allowed to cool to rt, was diluted withEtOAc and washed with water. The org. extracts were dried over MgSO₄,filtered and the solvents were removed under reduced pressure.Purification of the residue by FC (EtOAc/heptane 1:4-3:7) led to thetitle compound (5.23 g, 83%).

4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2-dihydro-5H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (G)

To a sol. of compound F (5.23 g, 10.3 mmol) in EtOH (90 mL) was addedaq. 1 M NaOH (90 mL). The resulting mixture was stirred for 35 min at80° C., then allowed to cool to rt. Aq. 1M HCl (13 mL) was added and theresulting mixture was extracted with EtOAc (3×). The combined org.extracts were dried over MgSO₄, filtered and the solvents were removedunder reduced pressure. Purification of the residue by FC (EtOAc/heptane2:3) led to the title compound (4.55 g, 89%).

Preparation of the Final Compounds

General Procedure A for Amide Coupling

A sol. of the desired carboxylic acid (1.00 eq), the desired amine (2.00eq), EDC-HCl (1.10 eq.), HOBt (cat. amount), DMAP (cat. amount) andDIPEA (2.00 eq.) in CH₂Cl₂ (20 mL/g of acid) was stirred at rtovernight. The reaction mixture was washed over diatomic earth (IsoluteSorbent Technology, Johnson, C. R., et al., Tetrahedron, 1998, 54, 4097)and the org. extracts were evaporated under reduced pressure. Theresidue was used without further purification.

General Procedure B for the Removal of a Boc-Protecting Group

The starting material was dissolved in CH₂Cl₂ (10 mL/g of startingmaterial) and the sol. was cooled to 0° C. 4M HCl in dioxane (samevolume as CH₂Cl₂) was added and the reaction mixture was left for 90 minat rt. The solvents were removed under reduced pressure. Purification ofthe residue by HPLC led to the desired compound.

General Procedure C for Reductive Amination

To a solution of aldehyde (1 eq.) in MeOH (0.5 mL/mmol) was added anamine (1.2 eq.). The solution was stirred for 2 h. Sodium borohydride(1.2 eq.) was added portionwise at 0° C. and then stirring wascontinued, at rt, for 4 h. A sol. of aq. 1M NaOH was added and the MeOHwas evaporated. The mixture was extracted with EtOAc twice and theorganic layer was washed with brine, dried over Na₂SO₄ and filtered. Thesolvent was removed under reduced pressure. The isolated amines wereeither used without further purification or purified by flashchromatography (EtOAc/heptane: 2/8), depending on the purity.

Preparation of the Secondary Amines

Cyclopropyl(2-fluorobenzyl)amine

Synthesized according to general procedure C from 2-fluorobenzaldehydeand cyclopropylamine.

(2-Chlorobenzyl)cyclopropylamine

Synthesized according to general procedure C from 2-chlorobenzaldehydeand cyclopropylamine.

(2-Chlorobenzyl)ethylamine

See Ishihara, Y; et al.; Chem. Pharm. Bull., 1991, 39, 3225.

Cyclopropyl-(2-fluoro-5-methoxybenzyl)amine

Synthesized according to general procedure C from2-fluoro-5-methoxybenzaldehyde and cyclopropylamine.

Cyclopropyl-(3-methoxybenzyl)amine

Synthesized according to general procedure C from 3-methoxybenzaldehydeand cyclopropylamine.

Cyclopropyl-(2-methoxybenzyl)amine

Synthesized according to general procedure C from 2-methoxybenzaldehydeand cyclopropylamine.

Cyclopropyl-(5-fluoro-2-methoxybenzyl)amine

Synthesized according to general procedure C from5-fluoro-2-methoxybenzaldehyde and cyclopropylamine.

(2-Chloro-6-fluorobenzyl)cyclopropylamine

Synthesized according to general procedure C from2-chloro-6-fluorobenzaldehyde and cyclopropylamine.

(2-Bromobenzyl)cyclopropylamine

Synthesized according to general procedure C from 2-bromobenzaldehydeand cyclopropylamine.

Cyclopropyl-(2,3-dimethylbenzyl)amine

Synthesized according to general procedure C from2,3-dimethylbenzaldehyde and cyclopropylamine.

(3,5-Bistrifluoromethylbenzyl)cyclopropylamine

Synthesized according to general procedure C from3,5-bistrifluoromethylbenzaldehyde and cyclopropylamine.

(2-Chloro-3,6-difluorobenzyl)cyclopropylamine

Synthesized according to general procedure C from2-chloro-3,6-difluorobenzaldehyde and cyclopropylamine.

Cyclopropyl-(3-methylbenzyl)amine

Synthesized according to general procedure C from 3-methylbenzaldehydeand cyclopropyl amine.

EXAMPLES Example 1(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluorobenzyl)amide

Prepared according to the general procedures A and B withcyclopropyl-(2-fluorobenzyl)amine. LC-MS: R_(t)=0.93; ES+: 539.21.

Example 2(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide

Prepared according to the general procedures A and B with(2-chlorobenzyl)ethylamine. LC-MS: R_(t)=0.94; ES+: 543.17.

Example 3(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylaniide

Prepared according to the general procedures A and B with(2-chlorobenzyl)cyclopropylamine. LC-MS: R_(f)=0.94; ES+: 555.19.

Example 4(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide formate salt

Prepared according to the general procedures A and B with cyclopropyl(2-fluoro-5-methoxybenzyl)amine. LC-MS: R, =0.94; ES+: 569.14.

Example 5(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide formate salt

Prepared according to the general procedures A and B with cyclopropyl(3-methoxybenzyl)amine. LC-MS: R_(f)=0.93; ES+: 551.18.

Example 6(rac.)-4-(4-[3-(2,3,6-Trinfluorophenoxy)propyl]phenyl)-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-methoxybenzyl)amide formate salt

Prepared according to the general procedures A and B with cyclopropyl(2-methoxybenzyl)amine. LC-MS: R_(t)=0.94; ES+: 551.18.

Example 7(rac-)-4-{4-[3-(2,3,6Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(5-fluoro-2-methoxybenzyl)amide formate salt

Prepared according to the general procedures A and B with cyclopropyl(5-fluoro-2-methoxybenzyl)amine. LC-MS: R_(f)=0.95; ES+: 569.15.

Example 8(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-Sfluorobenzyl)cyclopropylamide formate salt

Prepared according to the general procedures A and B with(2-chloro-6-fluorobenzyl)cyclopropylamine. LC-MS: R_(t)=0.95; ES+:573.10.

Example 9(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

Prepared according to the general procedures A and B with(2-bromobenzyl)cyclopropylamine. LC-MS: R_(f)=0.96; ES+: 599.04.

Example 10(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

Prepared according to the general procedures A and B withcyclorpopyl-(2,3-dimethylbenzyl)amine. LC-MS: R_(f)=0.97; ES+: 549.17.

Example 11(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]-henyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid (3,5-bistrifluoromethylbenzyl)cyclopropylamide formate salt

Prepared according to the general procedures A and B with(3,5-bistrifluromethylbenzyl)cyclopropylamine. LC-MS: R_(f)=1.00; ES+:657.13.

Example 12(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3,6-difluorobenzyl)cyclopropylamide-formate salt

Prepared according to the general procedures A and B with(2-chloro-3,6-difluorobenzyl)cyclopropylamine. LC-MS: R_(t)=0.96; ES+:591.12.

Example 13(rac.)-4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methylbenzyl)amide formate salt

Prepared according to the general procedures A and B withcyclopropyl-(3-methylbenzyl)amine. LC-MS: R_(t)=0.95; ES+: 535.19.

The following assay was carried out in order to determine the activityof the compounds of general formula I and their salts.

Inhibition of Human Recombinant Renin by the Compounds of the Invention

The enzymatic in vitro assay was performed in 384-well polypropyleneplates (Nunc). The assay buffer consisted of 10 mM PBS (Gibco BRL)including 1 mM EDTA and 0.1% BSA. The incubates were composed of 50 μLper well of an enzyme mix and 2.5 μL of renin inhibitors in DMSO. Theenzyme mix was premixed at 4° C. and consists of the followingcomponents:

human recombinant renin (0.16 ng/mL)

synthetic human angiotensin(1-14) (0.5 μM)

hydroxyquinoline sulfate (1 mM)

The mixtures were then incubated at 37° C. for 3 h.

To determine the enzymatic activity and its inhibition, the accumulatedAng I was detected by an enzyme immunoassay (EIA) in 384-well plates(Nunc). 5 μL of the incubates or standards were transferred to immunoplates which were previously coated with a covalent complex of Ang I andbovine serum albumin (Ang 1-BSA). 75 μL of Ang I-antibodies in assaybuffer above including 0.01% Tween 20 were added and a primaryincubation made at 4° C. overnight. The plates were washed 3 times withPBS including 0.01% Tween 20, and then incubated for 2 h at rt with anantirabbit-peroxidase coupled antibody (WA 934, Amersham). After washingthe plates 3 times, the peroxidase substrate ABTS(2.2′-azino-di-(3-ethyl-benzthiazolinsulfonate), was added and theplates incubated for 60 min at rt. After stopping the reaction with 0.1M citric acid pH 4.3 the plate was evaluated in a microplate reader at405 nm. The percentage of inhibition was calculated of eachconcentration point and the concentration of renin inhibition wasdetermined that inhibited the enzyme activity by 50% (IC₅₀). TheIC₅₀-values of all compounds tested are below 1 μM. Selected compoundsexhibit a very good bioavailibility and are metabolically more stablethan prior art compounds.

1. A compound of formula I

wherein X and W represent independently a nitrogen atom or a CH-group; Vrepresents —(CH₂)_(r)—; -A-(CH₂)_(s)—; —CH₂-A-(CH₂)_(t); —(CH₂)_(s)-A-;—(CH₂)₂-A-(CH₂)_(u)—; -A-(CHF)_(v)—B—; —CH₂—CH₂—CH₂-A-CH₂—;-A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH—B—; —CH₂—CH₂—CH₂-A-CH₂—CH₂—;—CH-2-CH₂—CH₂—C₁₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—CH₂—; —CH₂-A-CH₂—CH₂—B—CH₂—;—CH₂-A-CH₂—CH₂—CH₂—B—; or —CH₂—CH₂-A-CH₂—CH₂—B—; A and B independentlyrepresent —O—; —S—; —SO—; or —SO₂—; U represents aryl; or heteroaryl; Trepresents —CONR¹—; —(CFL)_(p)OCO—; —(CH₂)_(p)N(R¹)CO—;—(CH₂)_(p)N(R¹)SO₂—; —COO—; —(CH₂)_(p)OCONR¹—; or—(CH₂)_(p)N(R¹′)CONR¹—; Q represents lower alkylene; or loweralkenylene; M represents hydrogen; cycloalkyl; aryl; heterocyclyl;heteroaryl; aryl-O(CH₂)_(v)R²; heteroaryl-O(CH₂)_(v)R²;aryl-O(CH₂)₂O(CH₂)_(w)R²; heteroaryl-(CH)₂O(CH)_(w)R²;aryl-OCH₂CH(R₅)CH²; or heteroaryl-OCHCH(R⁵)CH₂R²; R¹ and R¹′independently represent hydrogen; lower alkyl; lower alkenyl; loweralkinyl; cycloalkyl; aryl; or cycloalkyl-lower alkyl; R² represents —OH,lower alkoxy, —OCOR³, —COOR³, —NR³R³, —OCONR³R³′, —NCONR³R³′, cyano,—CONR³R³′, SO₃H, —SONR³R³¹, —CO-morpholin-4-yl,—CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH₂, or —NR⁴R⁴′, with theproviso that a carbon atom is attached at the most to one heteroatom incase this carbon atom is sp³-hybridized; R³ and R³′ independentlyrepresent hydrogen; lower alkyl; lower alkenyl; cycloalkyl; orcycloalkyl-lower alkyl; R⁴ and R⁴′ independently represent hydrogen;lower alkyl; cycloalkyl; cycloalkyl-lower alkyl; hydroxy-lower alkyl;—COOR²; or —CONe; R⁵ represents —OH, —OR²; —OCOR²; —OCOOR²; or R⁵ and R²form together with the carbon atoms to which they are attached a1,3-dioxolane ring which is substituted in position 2 with R³ and R³′;or R⁵ and R² form together with the carbon atoms to which they areattached a 1,3-dioxolan-2-one ring; p is the integer 1, 2, 3 or 4; r isthe integer 3, 4, 5, or 6; s is the integer 2, 3, 4 or 5; t is theinteger 1, 2, 3 or 4; u is the integer 1, 2 or 3; v is the integer 2, 3or 4; and w is the integer 1 or 2L or optically pure enantiomers,racemates, diastereomers, mixtures of diastereomers, diastereomericracemates, mixtures of diastereomeric racemates, or the meso-form of thecompound; or pharmaceutically acceptable salts, solvent complexes ormorphological forms of the compound.
 2. The compound of formula Iaccording to claim 1, wherein T represents —CONR¹—; Q represents amethylene; and M represents aryl; heteroaryl; aryl-O(CH₂)_(v)R²; orheteroaryl-O(CH₂)_(v)R², or optically pure enantiomers, racemates,diastereomers, mixtures of diastereomers, diastereomeric racemates,mixtures of diastereomeric racemates, or the meso-form of the compound;or pharmaceutically acceptable salts, solvent complexes or morphologicalforms of the compound.
 3. The compound of formula I according to claim1, wherein V represents —CH₂CH₂O—; —CHC²CH₂O—; or —OCHCH₂O—, oroptically pure enantiomers, racemates, diastereomers, mixtures ofdiastereomers, diastereomeric racemates, mixtures of diastereomericracemates, or the meso-form or the compound; as or pharmaceuticallyacceptable salts, solvent complexes or morphological forms of thecompound.
 4. The compound of formula I according to claim 1, wherein Xand W represent —CH—, or optically pure enantiomers, racemates,diastereomers, mixtures of diastereomers, diastereomeric racemates,mixtures of diastereomeric racemates, or the meso-form of the compound;or pharmaceutically acceptable salts, solvent complexes or morphologicalforms of the compound.
 5. The compound of formula I according to claim1, wherein U represents a mono-, di-, or trisubstituted phenyl orheteroaryl, wherein the substituents are independently selected from thegroup consisting of halogen, lower alkyl, lower alkoxy, and CF₃. oroptically pure enantiomers, racemates, diastereomers, mixtures ofdiastereomers, diastereomeric racemates, mixtures of diastereomericracemates, or the meso-form of the compound; or pharmaceuticallyacceptable salts, solvent complexes or morphological forms of thecompound.
 6. The compound according to claim 1 selected from the groupconsisting of(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluorobenzyl)amide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-methoxybenzyl)amide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(5-fluoro-2-methoxybenzyl)amide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid (2-chloro-6-fluorobenzyl)cyclopropylamide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]-henyl}-1,2,3,6-tetrahydro-pyridine-3-carboxylicacid (3,5-bis-trifluoromethylbenzyl)cyclopropylamide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid (2-chloro-5-trifluoromethylbenzyl)cyclopropylamide;(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3,6-difluorobenzyl)cyclopropylamide; and(rac.)-4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,3,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methylbenzyl)amide.
 7. A pharmaceutical compositioncomprising at least one compound of claim 1 and a carrier and/or anadjuvant.
 8. A method for the treatment or prophylaxis of RAS-associateddiseases comprising hypertension, congestive heart failure, pulmonaryhypertension, cardiac insufficiency, renal insufficiency, renal ormyocardial ischemia, atherosclerosis, renal failure, erectiledysfunction, glomerulonephritis, renal colic, glaucoma, diabeticcomplications, complications after vascular or cardiac surgery,restenosis, or complications of treatment with immunosuppresive agentsafter organ transplantation, which method comprises administering thecompound according to claim 1 to a subject.
 9. (canceled)
 10. (canceled)11. A pharmaceutical composition comprising at least one compound ofclaim 6 and a carrier and/or adjuvant.
 12. A method for the treatment orprophylaxis of RAS-associated diseases comprising hypertension,congestive heart failure, pulmonary hypertension, cardiac insufficiency,renal insufficiency, renal or myocardial ischemia, atherosclerosis,renal failure, erectile dysfunction, glomerulonephritis, renal colic,glaucoma, diabetic complications, complications after vascular orcardiac surgery, restenosis, or complications of treatment withimmunosuppresive agents after organ transplantation, which methodcomprises administering the compound according to claim 6 to a subject.